“We’ve known for decades that in some cases there is an association between karyotypic or gross chromosomal changes and stillbirths,” said Dr. Kjersti Aagaard, assistant professor of obstetrics and gynecology at BCM and corresponding author of the report. “In this study, we found very small deletions and duplications (in the genomes) of the placentas of stillborn fetuses.”
Stillbirth occurs at a rate of about 1 in 160 live births. Some can be traced to obvious malformations in fetal development, maternal or fetal infections, defects in formation of the placenta or umbilical cord, or chronic illness in the mother. However, there is no known cause for as many as 60 percent of stillbirths, a tragic occurrence in the life of any mother, her partner, and the family.
In this study, Aagaard and her colleagues from The University of Texas Medical Branch in Galveston and the University of Modena and Reggio Emilia in Italy examined over 60 stillbirths delivered at Policlinico Hospital of Modena, Italy.
Comparing tiny genome changes
Using rigorous criteria they identified from these a subset of 29 that a panel of physician experts classified as “unexplained” and without evidence of large chromosomal abnormalities. They obtained placental and fetal or infant tissue and the mother’s blood where possible. They also obtained genomic DNA from 10 live-born infants and their placentas for comparison. They then used a number of high-resolution array techniques to look for small, submicrosopic structural changes called copy number variations, as well as single nucleotide polymorphisms (or single base pair DNA changes).
These techniques (called CNV-SNP arrays and comparative genomic hybridization) allow the researchers to look for tiny changes in the genome by comparing it to a known genome.
They found 24 new copy number variations in the group. Further tests confirmed 18 of these in the placental samples and eight were confirmed in the fetal samples. None was found in the maternal blood. In one case, a deletion in the genome obliterated 25 genes – leading researchers to believe that is almost surely the cause of the stillbirth.\Alterations in genetic material
“Among these cases of stillbirth that have no evidence of anomalies, infection or maternal disease, our results suggest that physicians may find considerable alteration in genetic material,” said Aagaard.
The use of the technique has important implications because it does not require growing cells from the fetus to do the studies, she said.
“We have observed that we were able to perform high-quality genetic analysis without growing cells,” she said. “We have also shown that placental material largely shares the fetal gene sequences, which — implies that we do not have cells from the fetus. This is of great importance in some clinical situations, and may better abide by the preferences of some parents during times of tremendous strife and grief.”
In this study, the duplications or deletions in the genome of the placenta or fetus were not found in the mother. That could mean that they are new to this particular fetus and not something passed from mother to child.
“In those cases of a de novo or new deletion, we would not have to engage the mother in testing for this in future pregnancies,” said Aagaard. “This might offer a level of assurance to these moms, and may in the future enable us to cut back on unnecessary and anxiety provoking testing in subsequent pregnancies.”
However, in cases where mothers and fetuses carry the same deletions or duplications, physicians might want to offer such testing and could do so early in pregnancy with a sampling of the placenta (chorionic villus sampling).
“We were very fortunate to provide the genetic tools and science for what is the first large study completed on well-characterized, and therefore truly unexplained stillbirths. We hope that our findings will make an impact on the field, and improve our ability to provide care for families with stillbirths. While our immediate goal was to demonstrate that high resolution genetic testing may be feasible and worthwhile, our true aim is to provide optimal genetic tools to help guide women and their families in a terribly difficult and tragic time of their lives,” she said.
Others who took part in this work include Dr. R. Alan Harris, Dr. Shay Ben-Shachar, Xiaoling Wang and Dr. Ignatia Van Den Veyver of BCM, Dr. George Saade, Dr. Francesca Ferrari and Fabio Facchinetti of the University of Modena and Reggio Emilia.
Funding for this work came from the National Institutes of Health New Innovator Award to Aagaard.
A link to the study is available.